The formation of carbon--carbon bonds remains among the most important reactions in synthetic organic chemistry. Consequently, the development of transition metal catalyzed carbon--carbon bond formation represented a significant advance in organic synthesis. One reaction involving transition metal catalyzed carbon--carbon formation is olefin metathesis. Olefin metathesis can be defined conceptually as a mutual exchange of alkylidene units between two olefins involving both the formation and cleavage of carbon--carbon double bonds. Transition metal ion catalysts allow this reaction to proceed in a facile manner through a [2+2] cycloaddition between an M.dbd.C center and a carbon--carbon double bond. When two olefin groups are located on the same molecule and are subjected to olefin metathesis conditions, a ring-closing metathesis (RCM) reaction can occur in which a series of olefin metathesis reactions produce a cyclic olefin. Ring-closing metathesis is most facile for 5-7 membered ring systems because of the low ring strain afforded by these compounds. Ruthenium and molybdenum alkylidene complexes have proven capable of ring closing dienes having a variety of functional groups.
RCM reactions are generally plagued by undesirable reactions that compete with ring formation, such as acyclic diene metathesis and ring opening metathesis. The former reaction involves polymer formation through the metathesis of terminal dienes whereas the latter reaction comprises metathesis reactions of the ring-closed cyclic olefin. These competing reactions can be circumvented, for example, by performing the reactions under dilute conditions, optimizing ring sizes and utilizing hindered olefin substrates. The latter strategy is also useful for directing the initial reaction of the metal alkylidene towards one olefinic site in a diene over the other olefinic group.
The development of asymmetric ring closing metathesis has considerable potential as a powerful synthetic tool for the preparation of ring structures of defined stereosymmetry. For example, a logical application of asymmetric RCM is the synthesis of natural products which contain varying sizes of ring systems having pendant functional groups of specific stereosymmetry. U.S. Pat. No. 5,516,953 discloses a process for the preparation of optically active cycloolefins catalyzed by molybdenum and tungsten complexes. This process requires that substrate be initially isolated as an optically active diene. Olefin metathesis is catalyzed by molybdenum and tungsten halide or oxide complexes that may also contain alkoxide or amido ligands. In some instances, a tin, lead, aluminum, magnesium or zinc complex cocatalyst may be required.
U.S. Pat. No. 4,654,462 describes a process for olefin metathesis by a tungsten complex containing two phenoxy groups, a halogen atom, an alkyl radical and a carbene. Stereoselectivity is reported sufficient to control cis/trans isomerization in the metathesis of pure cis or trans olefins.
Only recently, the first report of an asymmetric RCM reaction involving the interaction of a chiral catalyst with a racemic substrate mixture was reported by Grubbs et al. J. Am. Chem. Soc. 1996, 118, 2499, Organometallics 1996, 15, 1865. A racemic diene substrate was added to a molybdenum alkylidene amido catalyst containing a dialkoxide ligand. At various conversion levels of the starting mixture, the enantiomeric excess of the unreacted diene mixture was analyzed, resulting in enantiomeric excess values of up to 48%. The enantiomeric excess of the ring-closed product was not reported. It was proposed that the dialkoxide had a rigid structure suitable to promote the transfer of asymmetry.
There remains a fundamental need for the synthesis of optically pure products by using asymmetric ring-closing metathesis reactions. In a recent review article, Blechert et al. discuss the state of the art relating to asymmetric RCM reactions, maintaining that "In light of the e.e. [enantiomeric excess] values obtained to date, synthetic applications of this process are currently not envisioned." Angew. Chem., Int. Ed. Engl. 1997, 36, 2036. Asymmetric processes only begin to show promise industrially when achieving enantiomeric excess values of at least 80%.
It remains a challenge to design a metal catalyst that can produce ring structures of various sizes and pendant functional groups while achieving high enantioselectivity.